Stanton was drafted by the Atlanta Braves and he made his major league debut in 1989 with the Braves, where he spent the first six years of his career. He pitched in 20 games his first year, racking up 27 strikeouts and seven saves. Stanton struggled mightily in his sophomore season, going 0–3 with an ERA of 18.00 in just seven innings (giving up 14 runs).[4] 1991 was his first year as a full-time player, and he put up a 5–5 record in 74 games, earning a spot on the postseason roster. He pitched well, allowing just one run in eight total games, including a victory in the 1991 World Series. In 1992, he went 5–4, (his first season with a record over .500).[4] The Braves once again lost the World Series, this time to the Toronto Blue Jays, as Stanton allowed three hits and two walks during the series. The next year, he fashioned a 4–6 record with a in 63 games, but earned a career-high 27 saves.[4] He pitched one inning of one-hit, one-walk baseball in the 1993 National League Championship Series. In 1994, Stanton fashioned a 3–1 record before the strike ended the season early. He was granted free agency following the season, but re-signed on April 12, 1995. When play resumed in 1995, Stanton pitched in 26 games, garnering a 1–1 record and 5.59 ERA before being traded on July 31 to the Boston Red Sox.

Stanton pitched in 22 games with a 1–0 record and 3.00 ERA in 1995. He allowed one hit and struck out four in his only postseason appearance. In 1996, he fashioned a 4–3 record with a 3.83 ERA before being traded to the Texas Rangers.

Stanton pitched in 23 games while surrendering eight runs. In the 1996 American League Division Series, he pitched in three games, earning one loss and surrendering his only postseason home run.[4] On October 27, 1996, he was granted free agency, and he signed with the Yankees on December 11.

Stanton pitched for the New York Yankees for seven seasons. During that span, Stanton was a large part of the Yankees World Series teams, proving himself in big roles out of the bullpen. He garnered a 6–1 record in 1997, and appeared in 64 games.[4] In the 1997 American League Division Series, he allowed one hit in one inning while striking out three.[4] In 1998, Stanton went 4–1 and collected six saves during the Yankees' 114-win season. After not pitching in the Division Series, he returned during the Championship Series and allowed two hits and one walk while striking out four over three games.[4] In the 1998 World Series, Stanton allowed three hits and two earned runs.[4] Despite his lackluster performance, he earned a World Series ring as the Yankees swept the Padres four games to none. In 1999, he was 2–2 in 73 games, and did not pitch in the Division Series. In the Championship Series, he allowed one hit in 1/3 of an inning. However, he rebounded in the 1999 World Series, striking out the only batter he faced.[4] On November 5, he was granted free agency, but re-signed with the Yankees on November 29.[4] In 2000, he was 2–3 with a 4.10 ERA over 69 games. He pitched in four innings of one-hit ball in the Division Series and did not pitch in the Championship Series.[4] In the 2000 World Series, he earned two wins in four games. In 2001, he was 9–4 with a 2.58 ERA and was selected to the 2001 All-Star team. He pitched in all three games of the 2001 American League Division Series and in two games of the 2001 American League Championship Series. He pitched in five games of the 2001 World Series. His contributions in the postseason during this three-year period helped him post the lowest ERA in World Series history among relief pitchers. In 2002 he was 7–1 with a 3.00 ERA, and pitched in three games in the 2002 American League Division Series allowing three runs.[4] He was released on October 30.

Stanton was 2–1 with the Washington Nationals, finishing six games. On September 29, he was traded to the Boston Red Sox, where he pitched one inning of one-hit ball. He was released by the Red Sox on October 12.[4]

He re-signed with Washington on December 24 and was 3–5 with a 4.47 ERA in 56 games. On July 28, 2006 he was traded to the San Francisco Giants. He was 4–2 with the Giants over 26 games and was released on October 30. On November 20, 2006 he signed with the Cincinnati Reds.

With the Reds, he was 1–3 with a 5.93 ERA in 69 games. Despite his high salary due in 2008, the Reds cut Stanton from the team, going instead with veteran lefty Kent Mercker. The Reds would eat $3.5 million in salary to make the cut, including the 2008 salary and the 2009 option.[5] After being cut by the Reds, Stanton signed a minor league contract with an invitation to spring training with the Chicago Cubs on January 20, 2009. He did not make the team and was released on March 30.[6]

In his major league career, Stanton would post a 68–63 record with a 3.92 ERA and 84 saves in 1178 games pitched which ranks him second all-time in appearances behind Jesse Orosco (1252).

Mike Stanton is the all time holds leader, with 266. The hold is similar to the save, although it is not considered an official statistic. Arthur Rhodes is second on the list, with more than 40 fewer holds.